1. Field of the Invention
This invention relates to the fields of biology, medicine and oncology. In particular, the invention relates to the use of PI3-K helicase inhibitors to treat MUC1-expressing cancers.
2. Related Art
Mucin 1 (MUC1) is an oncoprotein that is aberrantly overexpressed in human cancers by mechanisms that are not clearly understood (Kufe, 2009). MUC1 consists of two subunits that form a non-covalent complex at the cell membrane (Kufe, 2009). The MUC1 N-terminal (MUC1-N) ectodomain is the mucin component of the heterodimer that contains glycosylated tandem repeats. The transmembrane MUC1 C-terminal subunit (MUC1-C) has a 58 amino acid (aa) extracellular domain that interacts with the epidermal growth factor receptor (EGFR) and other receptor tyrosines (Ramasamy et al., 2007; Kufe, 2009).
The 72 aa MUC1-C cytoplasmic domain binds to PI3-K and contributes to activation of the PI3-K→AKT pathway (Raina et al., 2004; Raina et al., 2011). Overexpression of the MUC1-C subunit, as found in diverse human cancers, is sufficient to induce anchorage-independent growth and tumorigenicity (Li et al., 2003; Huang et al., 2005; Kufe, 2009). Upregulation of MUC1-C also attenuates the induction of cell death in response to genotoxic, oxidative and hypoxic stress (Yin and Kufe, 2003; Ren et al., 2004; Yin et al., 2007). MUC1-C localizes to the nucleus, where it associates with transcription factors, such as NF-κB RelA and STAT3, and promotes activation of their target genes, including MUC1 itself (Ahmad et al., 2009; Ahmad et al., 2011). Thus. MUC1-C contributes, at least in part, to its own overexpression through autoinductive regulatory loops (Kufe, 2009).
Based on these findings, MUC1-C has emerged as an attractive target for cancer treatment using approaches that block its function and thereby overexpression. For example, cell-penetrating peptides and small molecules that inhibit the MUC1-C cytoplasmic domain attenuate localization of MUC1-C to the nucleus of cancer cells and downregulate its overexpression (Raina et al., 2009; Joshi et al., 2009; Zhou et al., 2011). There is, however, limited information about combining anti-MUC1-C therapies with other agents.